PROJECT ABSTRACT: The overall objectives of this research plan are to produce low profile endoluminal ultrasound applicators with deployable lens/reflector systems, in conjunction with real-time MRI guidance and MR temperature imaging (MRTI), to allow for localization and precise delivery of thermal ablation or hyperthermia in the treatment of pancreatic cancer. Pancreatic cancer is the fourth most deadly cancer in the USA, with only ~20% of patients eligible for surgery. Radiation therapy and chemotherapy remain the standard of care, but have modest improvements to survival and significant morbidity. Recent clinical studies indicate thermal therapies may provide palliation, reduce tumor burden, and increase survival. Extracorporeal High-Intensity Focused Ultrasound (HIFU) systems can deliver precision pancreatic tumor ablation, although there are limitations with respect to tumor size, accessible locations, damage to adjacent tissues, and an inability to deliver deep volumetric hyperthermia into the abdomen. Recent laboratory and clinical studies support a possible role for hyperthermia therapy as an adjunct to radiation, chemotherapy, targeted drug release, and immunotherapies. Our expertise and experience developing ultrasonic devices and techniques for MR guided thermal therapy, along with preliminary data, indicate that ultrasound applicators with deployable assemblies, positioned within the stomach or duodenum under MR guidance, are feasible and have potential to provide the means to deliver precision ablation and hyperthermia for the treatment of pancreatic cancer. These innovative reflector/lens balloon systems allow the ultrasound applicators to be positioned with MR guidance in a body lumen under low profile, and then deployed and expanded when in position to produce a larger acoustic aperture for deeper focusing or volumetric hyperthermia, expanding the range and utility of this approach. The goals of this project are: (1) to apply theoretical and advanced experimental design to develop forward-fire and side-fire ultrasound deployable reflector/lens assemblies suitable for endoluminal insertion into the stomach or duodenum, and optimized for penetration and spatial control required for localization of therapy; (2) to further develop acoustic and thermal computer simulations, apply 3D patient specific simulations to assess heating performance, design delivery strategies, and develop a treatment planning framework; (3) to develop MRI guidance and MRTI for accurate delivery and monitoring, using rapid acquisition with hybrid referenceless and multibaseline MR thermometry to accommodate physiologic organ motion; and (4) to perform in vivo studies of the deployable ultrasound applicators and MR guidance platform, and to use MRTI, contrast enhanced MRI, and histology to assess the ability and accuracy to target ablation and hyperthermia of pancreatic tissue while sparing adjacent tissues. Completion of this proposed study has potential to lead to a novel and accurate minimally-invasive method for treating pancreatic cancer with thermal therapy, with discretion to avoid damage to non-target tissues, and can be used alone or as a powerful adjunct to other therapies.